Imaging of DLPFC and amygdala impact on relative preference in cocaine addiction Abstract Relatively recently, studies of the relationship of brain structural measures and reward/aversion processing have started to appear. One challenge with studies showing altered brain structure in relationship to altered approach and avoidance behaviors in addiction is that it is difficult to interpret whether the findings relate to (i) vulnerability factors, (ii) effects of drug exposure/damage, or (iii) compensatory responses to the illness. From the literature, results regarding structure asymmetry, correlations with behavior, and responses to abstinence are emerging that suggest we can develop and test hypotheses that weight interpretation toward vulnerability, drug exposure/damage, or compensation. We propose to evaluate the relationship of brain structure with keypress measures of relative preference, including strongly aversive ones, and determine if findings can be extended to healthy controls, or related to vulnerability factors, signs of drug exposure, or compensatory responses in cocaine dependent polysubstance abusing (CDPA) subjects. We will specifically target the amygdala, insula (INS), and dorsolateral prefrontal cortex (DLPFC), given each of these regions has been functionally connected with keypress tasks related to judgment and decision-making based on relative preferences, or structurally connected with keypress tasks in CDPA subjects. We predict that alterations in: (1) the amygdala relate to vulnerability, (2) the INS relate to drug exposure, and (3) the DLPFC relate to compensatory responses. These hypotheses will be tested by behavioral testing with keypress tasks and high- resolution MRI scanning of matched groups (N=80 each) who are (1) active CDPA subjects, (2) long-term abstinent CDPA subjects, and (3) healthy volunteers. Brain structure and behavior will be specifically tested for differences between these three groups, and for altered relationships between structure and behavior to draw inferences on (a) whether structural measures in the DLPFC, INS, and amygdala can be connected to keypress behavior to approach and avoid goal-objects in healthy controls, and (b) whether abnormalities in CDPA subjects can be interpreted in terms of vulnerability, drug exposure, or compensatory responses. PUBLIC HEALTH RELEVANCE: Imaging of DLPFC and amygdala impact on relative preference in cocaine addiction A fundamental feature of drug addiction, such as cocaine dependence, is that the addicted individual shows a reduced range and depth to their interests;referred to as the "restricted behavioral repertoire" of addiction, this critical feature can be analogized to an investor who only buys one stock, as opposed to distributing investment risk across a broad range of stocks. Pioneering studies have suggested this clinical feature may be connected to abnormalities in brain structures involved with making judgments and decisions about reward and that this behavior-structure relationship may be a predisposition to drug use. The current project will directly test if a broad set of brain structures involved with decision-making about reward, are also abnormal structurally, and associated with the behavioral abnormality in cocaine addiction. This project will also seek to determine if this behavior-structure abnormality is related to the drug use itself, or potentially has features indicating it predates the drug-use.